Severe neurodevelopmental phenotype, diagnostic, and treatment challenges in patients with SECISBP2 deficiency

Abstract

Purpose: Defects in the gene encoding selenocysteine insertion sequence binding protein 2, SECISBP2, result in global impaired selenoprotein synthesis manifesting a complex syndrome with characteristic serum thyroid function tests due to impaired thyroid hormone metabolism. Knowledge about this multisystemic defect remains limited.

Methods: Genetic and laboratory investigations were performed in affected members from 6 families presenting with short stature and failure to thrive.

Results: Four probands presented a complex neurodevelopmental profile, including absent speech, autistic features, and seizures. Pediatric neurological evaluation prompted genetic investigations leading to the identification of SECISBP2 variants before knowing the characteristic thyroid tests in 2 cases. Thyroid hormone treatment improved motor development, whereas speech and intellectual impairments persisted. This defect poses great diagnostic and treatment challenges for clinicians, as illustrated by a case that escaped detection for 20 years because SECISBP2 was not included in the neurodevelopmental genetic panel, and his complex thyroid status prompted antithyroid treatment instead.

Conclusion: This syndrome uncovers the role of selenoproteins in humans. The severe neurodevelopmental disabilities manifested in 4 patients with SECISBP2 deficiency highlight an additional phenotype in this multisystem disorder. Early diagnosis and treatment are required, and long-term evaluation will determine the full spectrum of manifestations and the impact of therapy.

Keywords: Neurodevelopmental disorder; SECISBP2; Selenoprotein; Short stature; Thyroid hormone metabolism defect.

Figure 1.. Pedigrees with thyroid function tests of the three families in which probands harbor compound heterozygous SECISBP2 variants. A) Family 1; B) Family 2; C) Family 3.

Subjects are identified by generation (roman numerals on the left) and by a number on the left of each symbol. Probands are indicated with an arrow. Males are shown as squares and females as circles. Results are aligned with each symbol representing a family member. All TFTs are without treatment. Values outside the normal range are indicated in bold numbers. GPx enzymatic activity (EA) and serum TT3/TT4 ratio are included. (NA, not available; TGab, antibodies against thyroglobulin; TPOab, antibodies against thyroid peroxidase. Age recorded is the age when the probands were referred and TFT were performed) described in Patients and Methods.

Figure 2.. Pedigrees and thyroid function tests of the three families in which probands harbor homozygous SECISBP2 variants. A) Family 4; B) Family 5; C) Family 6.

Subjects are identified by generation (roman numerals on the left) and by a number on the left of each symbol. Probands are indicated with an arrow. Males are shown as squares and females as circles. Results are aligned with each symbol representing a family member. All TFTs are without treatment. Values outside the normal range are indicated in bold numbers. GPx enzymatic activity (EA) and serum TT3/TT4 ratio (Family 4) and Free T3/FreeT4 ratio (Families 5 and 6) are included. The TT3/TT4 ratio in Family 4, is marked in brackets in individual II-1 as the genotype is not known and in mother II-2 as she was pregnant at the time of the TFTs which is expected to alter the serum levels of TT4 and TT3. (NA, not available; TGab, antibodies against thyroglobulin; TPOab, antibodies against thyroid peroxidase; Age recorded is the age when the probands were referred and TFT were performed).

Figure 3.

Graphic representation of the TT3/TT4 ratios as mean +/− SD in members of families 1, 2, 3 and 4. Normal family members are shown as circles, heterozygous, as diamonds and affected individuals with biallelic SECISBP2 defects as triangles. ** P value 0.0016, **** P value <0.0001.